The HPV Warriors

An unlikely trio of researchers has built
a vaccine that attacks the virus responsible for the No.
2 killer of womencervical cancer.

By Anne Bennett Swingle | Photographs by Keith Weller

More than 100 years ago, a young New York surgeon
named William Coley came upon the peculiar case of a German
immigrant with a bulging tumor in his neck. After a fourth
surgery, a terrible post-operative infection set in, and
for days, the patient lay near death in New York Hospital.
Miraculously, the patientís immune system kicked in and the
infection subsided. Even more remarkably, so did the tumor.

The case made a profound impact on Coley. Maybe,
he hypothesized, the immune system could be riled with a
vaccine so that it would ambush malignant cells just as though
they were germs. He would spend the next several decades
inoculating cancer patients with bacterial extracts (Coleyís
toxins) with spotty success, but he paved the way to the
brave new world of tumor immunology.

Recently the field has evolved from something
of a rogue scienceófull of hopes, hype and then dashed expectationsóto
one that holds real promise. Thatís because advances in molecular
biology have made it possible for scientists to figure out
new ways to bring about highly specific immune system attacks.

Nowhere is this new dynamism more apparent than
in the big lab on the fourth floor of the new Bunting-Blaustein
Cancer Research Building, where tumor immunologist Drew Pardoll
is leading a team of investigators who have developed a series
of genetically engineered, therapeutic vaccines against the
human papilloma virus, or HPV, a sexually transmitted virus
that causes practically every single case of cervical cancer.

Drew Pardoll with a
student in the lab.

As the latest members in a long line of Hopkins
physicians who have studied cervical cancer (beginning with
Richard TeLinde who led gynecology for 21 years starting
in 1939), this new generation of investigators represents
a serendipitous convergence of talent so dazzling that some
have said that if a vaccine for the cancer-linked virus canít
happen at Hopkins, it probably canít happen anywhere. But
while huge hopes are riding on this work, there also are
huge challenges conspiring to make this a particularly long
and winding road to the clinic.

The human papilloma virus comes in more than
100 varieties, from the innocuous strains that cause the
common wart to the approximately 30 types that live in the
genital tract, including about 10 to 15 that can cause cancer.
HPV is a persistent and stealthy invader. Because it can
live in the cells of the outer skin, it eludes safe-sex practices.
And since it rarely produces symptoms, few people with the
virus know they have it. In fact, up to 75 to 80 percent
of sexually active women worldwide are infected at some point.
Most infections resolve spontaneously. A small fraction,
though, develop into cervical cancer.

Cervical cancer is the number two killer of
women in the world, with approximately 500,000 cases annually.
Itís a disease mostly of the poor and disenfranchised, women
with no access to the Pap smears that detect cervical abnormalities.
Keerti Shah, a School of Public Health professor of molecular
microbiology and immunology who has been investigating cervical
cancer and its connection to HPV since the 1970s, led a worldwide
team of researchers who recently proved that practically
every single case of cervical cancer is caused by HPV

In the mid-1980s, Tzyy-Choou "T.-C."
Wu, a Taiwanese gynecologist just completing a masterís in
public health at Hopkins, began to train in Shahís division,
studying the molecular diagnostics of HPV and gradually realizing
its potential for immunotherapy. On their surfaces, HPV cells
have well-defined antigens, tiny bits of protein that differentiate
them from normal cells, red flags that prompt the immune
system to attack. These antigens, called E6 and E7, are known
quantities, a dream come true, Wu thought, for the tumor
immunologist who could aim a cancer vaccine directly at them.

Closing in on cervical
cancer are (from left to right) T.-C. Wu, Drew
Pardoll and Connie Trimble.

In 1988, just as Wu was finishing up his Ph.D.
in molecular biology, Drew Pardoll returned to Hopkins after
a three-year fellowship at the National Institutes of Health.
Pardoll was interested in tumor immunology, a field still
considered a good one to avoid. He remembers that even his
advisers for his Ph.D. thesis, oncology researchers Bert
Vogelstein and Donald Coffey, agreed "that I would absolutely
destroy my career if I went into tumor immunology."
But Pardoll likes being outside the mainstream. "The
best time to go into an area is when other researchers have
left it for dead," Pardoll says.

Working at the very intersection of science
and philosophy, Pardoll was pondering why cancers, unlike
infections, spread without alerting the immune system, thinking
about how they appear as what scientists call "Self,"
cells that are so subtly altered they are overlooked by the
immune system. How to break this tolerance, he wondered?
How to alert the immune system that a tumor cell was really
foreign? Pardoll had begun a series of gene therapy studies,
but he didnít have what he needed most, the completely foreign,
reliably expressed antigens the immune system could target.

Wu, of course, knew of HPVís potential, of E6
and E7, and so he said to Pardoll, "If youíre so interested
in antigen-specific vaccines, then why arenít you working
on HPV?"

"I hardly knew what HPV was," recalls
Pardoll. And yet, the more he thought about it, the more
sense it made. In addition to having a very well-defined
tumor antigen, HPV provided an excellent opportunity to go
after early stage cancers instead of the more difficult bulky
tumors. Before long, Wu, encouraged by one of TeLindeís successors,
Bob Kurman, began tumor immunology training with Pardoll,
and the two were crafting a new generation of antigen-specific
cancer vaccines.

Vaccines have been the most successful medical
intervention in the history of human kind, but their success
against cancer has been elusive. Cancers generally are more
complicated than other diseases, and unlike a virus or a
bacteria, there is no simple bag of antigens with which to
make a vaccine.

Because one particular strain of papilloma virus,
HPV 16, accounts for over half the cases of cervical cancer,
Pardoll and Wu chose it as their target. For the first time
ever, Wu developed an animal model for the progression of
pre-invasive to invasive cervical cancer. (It is called "TC-1,"
for tissue culture number one, and T.-C.Wu can barely conceal
his delight that it incorporates his first name. "Suddenly,"
he says cheerfully, "Iíve become famous.")

The cell line expresses the E7 antigen, which
Wu and Pardoll wanted to make more visible to the immune
systemís tumor-fighting white blood cells, the so-called
"killer" T cells. "Imagine looking at a five-acre
field," says Pardoll. "If thereís one tulip in
the middle, youíre probably not going to see it. But if you
now have 100,000 tulips, theyíre very easy to see."

T cells would be blind to antigen were it not
for the special molecules, known as MHC molecules, on the
surface of cells that can see through cell walls and detect
the trespassers within. Working with Wuís mouse model, the
two scientists used a special sorting signal to reroute the
E7 antigen into a specific cellular compartment so that it
would become more visible to the MHC molecules and subsequently
to the "helper" T cells that initiate, coordinate
and oversee an overall immune response.

Linking the E7 gene to the sorting signal laid
the foundation for a series of approaches. The scientists
then fused the E7 antigen to a substance known as a "heat-shock"
protein, directly increasing the killer T cell response by
at least 30-fold. They also isolated a new gene responsible
for sending a co-stimulatory signal to activate the T cells.
Incorporating that signal has translated into even more powerful,
therapeutic vaccines.

"Building the best vaccine is kind of like
an erector set," says Pardoll. "You can keep adding
to it, and making it better. We could spend another 10 or
20 years building the biggest building, the best vaccine,
but for all we know, we already have it. The time to do the
human experiment is really now."

Trimble and Pardoll on the run.

Connie Trimble directs the cervical dysplasia
and colposcopy service, where patients with abnormal Pap
smears are diagnosed with a magnifying instrument, the colposcope,
and treated. In December 1997, Trimble was in her office
on Harvey 3 when Pardoll paid a call. In his lab, he explained,
he had a whole set of vaccines against HPV antigens under
development. For clinical trials, he needed what she hadópatients
with genital papilloma viruses who might benefit from these
novel vaccines.

Trimble was instantly intrigued. Like the other
leading researchers in the pathology of cervical diseases
who succeeded TeLinde, she possesses that rare combination
of training in gynecologic pathology and gyn. An energetic,
independent and curious woman, she is a translational researcher
at heart. Since the day she met Pardoll, she has schooled
herself on every aspect of the HPV vaccines, religiously
attending lab meetings, reading journal articles and taking
courses in immunology. When she was tapped as principal investigator
for the clinical trials, she determined to do more than just
pinpoint candidates for the vaccines. "I want to actually
know what Iím doing and not just be a hunter-gatherer,"
she says. "That is an incredibly offensive concept to
me."

To pave the way for a thoughtful selection of
patients, she established a Cervix Center for women with
abnormal Pap smears. Today, upwards of 400 patients annually
are treated by a core staff that includes colposcopists,
oncologists, pathologists and social workers. A Web site
about the center for area physicians who make referrals also
offers information to patients with cervical problems.

Last spring, after years of preparation, it
appeared that everything was at last in place for the long-awaited
human experiment. And yet, for months the trials stalled
as the NIH dragged its feet in funding the lab work. Industry,
which the researchers had counted on to support the trials,
was less enthusiastic, in part because cervical cancer is
seen as a disease of poor countries where few have the wherewithal
to pay for sophisticated therapies like this vaccine. Casting
a shadow over all was last yearís gene therapy death at the
University of Pennsylvania, a development that subjected
the project to unprecedented, stepped-up scrutiny.

Then, in midsummer, the Pardoll-Wu-Trimble ship
came in. The NIH announced that it was awarding the researchers
a $3.5 million Vaccine Center Grant to support the immunologic
studies in the lab. It also gave a five-year junior faculty
training grant to Trimble for translational research. A drug
company, meanwhile, stepped up to the plate to fund preliminary
vaccine trials.

By mid-July, Trimble had launched an initial,
observational trial with 15 patients receiving regular treatment.
By the end of the month, Hopkinsí Joint Commission on Clinical
Investigation was reviewing the protocol for the full study,
and the investigators were preparing to roll out their series
of vaccines, one by one.

If it demonstrates nothing else, the HPV vaccine
story shows the difficulties of translating research into
the clinic; itís been years since Wu developed his tumor
model and then worked with Pardoll to do the first successful
experiments with the vaccine in mice. But the story also
shows just how fast science today is galloping ahead of patient
treatment. Laboratory researchers have learned to diagnose
HPV with a simple molecular test, and appear to know how
to treat it with a vaccine, but physicians worldwide continue
to use their decades-old methods to diagnose and treat the
condition.

But Pardoll believes these HPV vaccines could play a
role in ushering in an immunologic revolution. One day, he says, vaccines
will be a first line of defense against cancer. "Iím betting my life
on it."